Abstract
The primary products of the metastasis-suppressor KiSS-1 gene are the kisspeptin (KP) peptides that stimulate gonadotrophin-releasing-hormone (GnRH) release via GPR-54 receptor activation. Recent studies have suggested that the KP-10 peptide also activates neuropeptide FF (NPFF) receptors. The aim of the current study was to determine the activities of the KiSS-1 derivative kissorphin (KSO), which contains the first six amino acids of the KP-10 peptide, is C-terminally amidated, and shares amino acid similarities with the biologically active NPFF 3–8 sequence. The KSO peptide inhibited forskolin-stimulated cyclic adenosine monophosphate (cAMP) production in ND7/23 neuroblastoma cells via an action that could be inhibited by the NPFF receptor antagonist RF9. Release of GnRH by LA-N-1 neuroblastoma cells was not altered by the KSO peptide. In ND7/23 neuroblastoma cells, the KSO peptide was able to reduce forskolin neuroprotection against H2O2 toxicity. The KSO peptide was also able to prevent prostaglandin E2-induced apoptosis in rat cortical neurons. The NPFF receptor antagonist RF9 could inhibit these actions of the KSO peptide in oxidative stress and apoptosis models. In conclusion, the kissorphin peptide, comprising the amino acid sequence Tyr-Asn-Trp-Asn-Ser-Phe-NH2, has NPFF-like biological activity without showing any GnRH releasing activity and inhibits forskolin-activated cAMP release.
Highlights
Recent studies have shown that kisspeptin (KP) peptides can activate the two neuropeptide FF (NPFF) receptors, NPFFR1 (GPR-147) and NPFFR2 (GPR-74) [1,2,3]
The NPFF-like biological activity was determined by measurement of forskolin-stimulated ir-cyclic adenosine monophosphate (cAMP) release in response to KSO, KP, and NPFF peptides
The NPFF, KP-10, and KP-13 peptides significantly inhibited forskolin stimulated ir-cAMP release, which could be antagonized by the NPFF receptor antagonist RF-9 [4] but not the GPR-54 receptor antagonist KP234 [39]
Summary
Recent studies have shown that kisspeptin (KP) peptides can activate the two neuropeptide FF (NPFF) receptors, NPFFR1 (GPR-147) and NPFFR2 (GPR-74) [1,2,3]. These actions of KP peptides can be blocked by NPFF receptor antagonists including RF9 [4]. The NPFF peptide is a ligand for both these receptors [5,6,7], and the biologically active NPFF 3– 8 form [8] shows amino acid sequence similarities to KP peptides (Table 1). Biological activity of KP peptides requires the KP 112-121 sequence with an amidated C-terminus [10, 13, 14]
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